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To compare the dose-response of remifentanil for tracheal intubation in infants and children, 32 healthy full-term infants and 32 children were anesthetized with 10 μg/kg glycopyrrolate and 4.0 mg/kg propofol and administered 1 of 4 doses of remifentanil (1.25, 1.50, 1.75, or 2.00 μg/kg) to facilitate tracheal intubation. We determined the effective doses of remifentanil in 50% (ED50) and 98% (ED98) of patients by using logistic regression analysis. We found that logistic regression curves were similar for infants and children (P = 0.38). ED50 and ED98 values for remifentanil were 1.70 ± 0.1 μg/kg and 2.88 ± 0.5 μg/kg, respectively. In a second double-blind study, 24 infants were anesthetized with propofol and randomized to receive either 3.0 μg/kg remifentanil or 2.0 mg/kg succinylcholine to facilitate tracheal intubation. The duration of apnea, tracheal intubating conditions and hemodynamic changes were determined. We found that the duration of apnea and intubating conditions after propofol/remifentanil were similar to those after propofol/succinylcholine. Bradycardia, hypotension, and chest wall rigidity did not occur. We conclude that the dose-response of remifentanil for tracheal intubation is similar in infants and children. Propofol/remifentanil provides clinically acceptable intubating conditions, stable hemodynamics, and a duration of apnea comparable to that with propofol/succinylcholine in infants.

IMPLICATIONS: The dose-response of remifentanil for tracheal intubation is similar in infants and children. In infants, coadministration of 4 mg/kg propofol and 3 μg/kg remifentanil provides clinically acceptable intubating conditions, stable hemodynamics, and a duration of apnea comparable to that after 4 mg/kg propofol and 2.0 mg/kg succinylcholine.

Department of Anaesthesia and the Research Institute, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada

The adverse effects of succinylcholine have limited its use and have prompted the investigation of alternative drugs to facilitate tracheal intubation. Coadministration of propofol and a short- or ultra-short-acting opioid has been used to facilitate tracheal intubation in adults and children undergoing elective surgery (1–9). This technique obviates the administration of a neuromuscular blocking drug and is advantageous in a variety of clinical situations (1–9). Although coadministration of propofol and the short-acting opioid alfentanil provides excellent conditions for tracheal intubation in children, the duration of action of alfentanil may be excessive for ambulatory surgery (2,7). Remifentanil has as rapid an onset of effect as alfentanil and has the advantage of an ultrashort duration of action (10).

The combined use of propofol and an opioid to facilitate tracheal intubation without a neuromuscular blocking drug has not been investigated in infants. We tested the hypothesis that the dose-response of remifentanil for tracheal intubation, when coadministered with 4.0 mg/kg propofol, is similar in healthy full-term infants and children. Then we compared the duration of apnea, tracheal intubating conditions, and hemodynamic changes after propofol/remifentanil with those after propofol/succinylcholine in a randomized double-blind study in full-term infants.

Methods

Research ethics board approval and informed written parental consent were obtained. Eighty-eight unpremedicated ASA class I or II pediatric patients scheduled to undergo elective general anesthesia that involved tracheal intubation were studied. Exclusion criteria were a history of reactive airway disease, gastroesophageal reflux, intracranial pathology, neuromuscular disease, developmental delay, use of medications that affect neuromuscular transmission, and a known or suspected difficult airway.

Study 1

To compare the dose-response of remifentanil for tracheal intubation in infants and children, 32 full-term infants aged 2–12 mo and 32 children aged 1–6 yr were studied. Each patient was randomized to receive 1 of 4 doses of remifentanil (1.25, 1.50, 1.75, or 2.00 μg/kg) to facilitate tracheal intubation. Randomization was achieved by using a schedule derived from a table of random numbers. A eutectic mixture of local anesthetics (EMLA®) was applied to the dorsum of a hand approximately 1 h before the insertion of a 22- or 24-guage IV catheter in the operating room. Standard intraoperative monitors were used. After the administration of 10 μg/kg glycopyrrolate, general anesthesia was induced with 4.0 mg/kg propofol to which 0.2 mg/kg lidocaine was added to prevent pain on injection. Immediately thereafter, the assigned dose of remifentanil was administered over 30 s by using a handheld syringe. Remifentanil was diluted in 0.9% saline to a volume of 10 mL. An anesthesiologist who was unaware of the dose assignment then ventilated the lungs with 100% oxygen by face mask and assessed for the presence of chest wall rigidity. Ninety seconds after the administration of remifentanil, the blinded anesthesiologist performed tracheal intubation with a straight-blade laryngoscope and an uncuffed orotracheal tube. Intubating conditions were graded with a scoring system based on criteria for good clinical research practice (Table 1) (11). Intubating conditions were excellent when all scores were 1, good when all scores were ≤2, and unacceptable if any score was ≥3. Scores of 1 and 2 were considered clinically acceptable. When intubating conditions were unacceptable, the lungs were ventilated with oxygen by face mask, and 0.6 mg/kg rocuronium was administered before a second attempt at intubation.

Study 2

Dose-response data from Study 1 indicated that remifentanil 3.0 μg/kg should provide clinically acceptable tracheal intubating conditions in >98% of patients. Therefore, to compare the duration of apnea, tracheal intubating conditions, and hemodynamic changes after propofol/remifentanil with those after propofol/succinylcholine, 24 healthy full-term infants aged 2–12 mo were randomly assigned to receive either 3.0 μg/kg remifentanil or 2.0 mg/kg succinylcholine to facilitate tracheal intubation. The primary outcome measure for this study was the duration of apnea. Randomization was achieved with a table of random numbers.

On arrival at the operating room, standard monitors were applied, nitrous oxide (70%) in oxygen was administered, and an IV catheter was inserted. Nitrous oxide was discontinued immediately after insertion of the catheter, and the patient awakened while breathing oxygen. Nitrous oxide was used to facilitate placement of the IV catheter because application of EMLA 1 h before surgery was not always feasible. All infants were awake and appeared to have recovered from nitrous oxide before the induction of anesthesia. General anesthesia was induced with 10 μg/kg glycopyrrolate and 4.0 mg/kg propofol to which 0.2 mg/kg lidocaine was added. Remifentanil or succinylcholine was diluted with 0.9% saline to a volume of 3 mL and administered as an IV bolus. A blinded anesthesiologist ventilated the lungs with 100% oxygen by mask and assessed for the presence of chest wall rigidity. Ninety seconds after the administration of remifentanil or succinylcholine, the blinded anesthesiologist intubated the trachea and graded intubating conditions as in Study 1. Time to tracheal intubation was recorded as the time from insertion of the laryngoscope blade into the oral cavity until tracheal intubation was complete. Anesthesia was maintained with oxygen and isoflurane at an inspired concentration of 1.0 minimum alveolar anesthetic concentration (age corrected) (12) until spontaneous ventilation returned, at which time 70% nitrous oxide was added to the inspired gas. Oxygen saturation was maintained more than 95% with assisted manual ventilation if required. The end-tidal carbon dioxide was measured from the first square capnograph wave form at the resumption of spontaneous ventilation. The duration of apnea was recorded. Heart rate, noninvasive arterial blood pressure, and oxygen saturation were recorded immediately after the induction of anesthesia and at 1-min intervals after tracheal intubation for 5 min, at which point the study ended. Bradycardia was defined as a heart rate <100 bpm for >60 s and hypotension as a systolic blood pressure <60 mm Hg.

In Study 1, the effective dose of remifentanil in 50% (ED50) and 98% (ED98) of patients was determined by using a logistic regression model in which P, the probability of successful tracheal intubation, is

where X1 is the indicator for age group (infant or child), X2 is the dose of remifentanil, β0 is the regression intercept constant, β1 is the coefficient for the effect of age group, and β2 is the coefficient for the effect of dose. The likelihood ratio test was used to determine the P value of the main effects (age group and dose).

To determine the ED50, the probability of successful tracheal intubation was evaluated at P = 0.5. Solving Equation 1 for X2 yields

To determine ED98, the probability of successful tracheal intubation was evaluated at P = 0.98, and the equation was solved for X2.

To estimate the sample size required for Study 2, we performed a pilot study in 10 full-term infants administered 2.0 mg/kg succinylcholine to facilitate tracheal intubation. We found that the duration of apnea after succinylcholine was 4.7 ± 0.7 min. For β = 0.1 and α2 = 0.05, we estimated that 12 infants per treatment group would be needed to detect a 20% difference in the duration of apnea. Student's t-test for unpaired data was used for comparison of the duration of apnea, and Fisher's exact test was used for comparison of the proportion of excellent or good intubating conditions. Two-way analysis of variance for repeated measures was used to analyze hemodynamic variables followed by pairwise multiple comparisons with the Student-Newman-Keuls test. All statistical tests were two tailed. Data are mean ± sd. P < 0.05 was considered statistically significant.

Results

Study 1

The mean age and weight of infants and children are shown in Table 2. Most patients were boys undergoing urological procedures. The proportion of excellent and good intubating conditions increased as the dose of remifentanil increased (P < 0.001) (Fig. 1). At 1.25, 1.50, 1.75, and 2.00 μg/kg remifentanil, the incidence of excellent or good intubating conditions was 13%, 38%, 50%, and 75% in infants and was 13%, 38%, 75%, and 89% in children, respectively. The logistic regression curve for infants did not differ significantly from that for children (P = 0.38) (Fig. 2). Variable estimates are shown in Table 3. Analysis of the combined data yielded ED50 and ED98 values of 1.7 ± 0.1 μg/kg and 2.88 ± 0.5 μg/kg, respectively.

Study 2

The mean age and weight of infants are shown in Table 2. Intubating conditions were excellent or good in all infants. Of the 12 infants administered remifentanil, intubating conditions were excellent in 11 and good in 1. For this one infant, the mandible was relaxed, the laryngoscope was inserted easily, the vocal cords were open and immobile, and there was a single cough but no movement of the extremities in response to intubation. Intubating conditions were excellent in all infants given succinylcholine (P > 0.05 compared with remifentanil). The duration of apnea after the administration of remifentanil (4.3 ± 1.1 min) did not differ significantly from that for succinylcholine (4.4 ± 0.7 min) (95% confidence interval of the difference = −0.7 to 0.8 min). There was no significant difference between groups in the time for tracheal intubation (remifentanil, 15 ± 3 s; succinylcholine, 13 ± 3 s) or the end-tidal carbon dioxide at the resumption of spontaneous ventilation (remifentanil, 55 ± 7 mm Hg; succinylcholine, 57 ± 6 mm Hg).

Heart rate at 3, 4, and 5 min after intubation in infants receiving remifentanil was significantly less than the corresponding values in the succinylcholine group (Fig. 3). Mean arterial blood pressure at 3, 4, and 5 min after intubation was significantly less than the baseline value in the remifentanil group but did not differ significantly from corresponding values in the succinylcholine group (Fig. 3). There were no complications associated with tracheal intubation and no episodes of bradycardia, hypotension, chest wall rigidity, or fasciculations.

Discussion

The results indicate that the dose-response of remifentanil for tracheal intubation is similar in infants and children and that coadministration of 4.0 mg/kg propofol and 3.0 μg/kg remifentanil provides excellent or good conditions for tracheal intubation and stable hemodynamics in healthy full-term infants with normal airway anatomy. In addition, the duration of apnea after bolus administration of remifentanil (4.3 ± 1.1 minutes) is comparable to that after 2.0 mg/kg succinylcholine, thus reflecting remifentanil's brief redistribution half-time (10).

Given that the dose-response of remifentanil is similar in infants and children, our data might be expected to compare favorably to the results of previous studies in children. However, the incidence of successful tracheal intubation after coadministration of propofol and remifentanil has been variable, ranging from 70% of children given 2.0 μg/kg remifentanil and 3.5 mg/kg propofol to 80% of children given 1.0 μg/kg remifentanil and 4.0 mg/kg propofol (7–9). Similarly, in adults, the effective dose of remifentanil when coadministered with 2.0–2.5 mg/kg propofol has ranged from 2.0 to 5.0 μg/kg (3–6). In addition to the dose-related effects of the drugs, factors that might affect the incidence of successful intubation after propofol and remifentanil include the sequence of drug administration and the timing of tracheal intubation in relation to the peak drug effect.

In designing our study, we considered it important that the peak effect of remifentanil should coincide with that of propofol to achieve the best possible intubating conditions. Remifentanil equilibrates relatively rapidly between plasma and the effect compartment, as demonstrated by its brief t1/2 keO (10). Given that equilibration of propofol with the effect compartment is slower (13), we administered the drugs in the sequence propofol/remifentanil. In support of this, a recent randomized study in adult patients reported that the incidence of successful tracheal intubation was significantly better when the order of drug administration was propofol/remifentanil compared with the reverse (14).

Additionally, the timing of tracheal intubation should coincide with the peak effects of propofol and remifentanil to achieve the best possible intubating conditions. The peak effect of remifentanil is achieved approximately 90 seconds after IV administration (10), and, thus, we performed laryngoscopy at 90 seconds. When laryngoscopy was performed at approximately 90 seconds in adults, the effective dose of remifentanil was 2.0 μg/kg (4), whereas up to double that dose was needed for laryngoscopy at 60 seconds (5), although other differences in study design might account for this discrepancy.

Because the depth of anesthesia at the time of tracheal intubation can influence conditions for tracheal intubation, we standardized the induction technique in these studies. Tracheal intubating conditions are generally unsatisfactory in unpremedicated children given 4.0 mg/kg propofol alone, and thus a control group given propofol alone was considered inadmissible. In keeping with our clinical practice, no sedative premedication was administered. Premedication with trimeprazine, a phenothiazine derivative that could potentially enhance the hypnotic effect of propofol, might explain in part the relatively small effective dose of remifentanil reported in a previous study (7).

Remifentanil, as with other potent opioids, may cause adverse cardiovascular effects, including bradycardia and hypotension—effects that might be dose independent in the case of remifentanil (10,15,16). In addition, dose- and rate of administration-dependent muscular rigidity has been reported in adults administered remifentanil during spontaneous ventilation (10,17). Accordingly, we pretreated our patients with glycopyrrolate and infused remifentanil over 30 seconds in the first study. However, we have found that bradycardia and chest wall rigidity are rare when the opioid is given after the induction of anesthesia with propofol and glycopyrrolate, and this is in agreement with the experience of others (18,19). Thus, to be consistent with the method of succinylcholine administration, we injected remifentanil as a bolus in the second study, because clinicians would tend to use this technique to minimize the time from the induction of anesthesia to tracheal intubation. A limitation of our study is that bolus administration rather than infusion over 30 seconds could have altered the dose effect of remifentanil, although it is unlikely that the difference in calculated ED values would be clinically significant. Indeed, intubating conditions were excellent or good in all infants in the second study, as anticipated from the results of the first. Although bradycardia and chest wall rigidity did not occur in the second study, heart rate was significantly slower in the remifentanil group as compared with the succinylcholine group, thus suggesting that remifentanil might have attenuated the hemodynamic response to tracheal intubation (20).

Various scoring systems have been used to assess intubating conditions in anesthetized subjects (11). We used a scoring system that is based on mandibular relaxation, ease of laryngoscopy, position and movement of the vocal cords, airway reaction, and movement of the extremities (11). Each of these variables was scored on a four-point scale, and scores of 1 and 2 were considered clinically acceptable. In all patients to whom we assigned 1 or more scores of 2, laryngoscopy was easy, the vocal cords were open, any cough was slight and did not impede passage of the tracheal tube, and any movement of the limbs was confined to the distal extremities.

In summary, the administration of 4.0 mg/kg propofol and 3.0 μg/kg remifentanil provided clinically acceptable conditions for tracheal intubation and stable hemodynamics in infants pretreated with glycopyrrolate. With this combination of drugs, the return of spontaneous ventilation was as rapid as after propofol/succinylcholine. This technique may be advantageous in infants with normal airway anatomy undergoing brief surgical procedures or in cases in which neuromuscular block is contraindicated; however, we do not recommend its use when immobility during tracheal intubation is crucial, such as in the presence of increased intracranial pressure.